Physicians in North America are more likely to treat hypothyroidism with combination therapy — by adding synthetic liothyronine (LT3) to the standard therapy of synthetic levothyroxine (LT4) replacement — compared with physicians in other countries.

This is despite conflicting guidelines on the practice, with many physicians seeming to make decisions in response to ongoing symptoms or patients' requests, according to new survey data.

"The results of this 2017 survey suggest that approximately one third of physicians taking care of patients with hypothyroidism are willing to prescribe therapies other than levothyroxine (LT4)," the authors say.

The inconsistent guidelines on combination therapy for hypothyroidism reflect inconclusive evidence on the relative risks and benefits, but with patients often reporting improvement with combination therapy, the controversial treatment approach is commonly used — and debated.

The 2012 and 2014 American Thyroid Association (ATA) guidelines for the treatment of hypothyroidism concluded that there was insufficient evidence to support routine prescribing of T3-containing therapies, but more recent recommendations from British and Italian societies, for example, indicate that T3-containing therapies "can be considered," say the researchers, led by Jacqueline Jonklaas, MD, PhD, assistant professor, Division of Endocrinology and Medicine, Department of Medicine, Georgetown University Medical Center, Washington, DC.

Jonklaas told Medscape Medical News that the survey findings of geographic differences in prescribing habits, as well as the notable recent changes, were unexpected.

"It was a surprise," she said. "We expected there to be similar prescribing trends across countries, or possibly more combination therapy prescribing in Europe."

Among the factors that may explain the shifting trends could include the timing of dissemination of the different guidelines, she suggested.

Survey Details

To take a closer look at the physician and patient characteristics associated with the prescription of combination therapy, Jonklaas and colleagues conducted a survey.

In the survey, physicians were presented with 13 different theoretical scenarios of patients with overt hypothyroidism and were asked to select among six therapeutic options, including LT4, synthetic combination therapy (LT4 plus LT3), desiccated thyroid extract (such as Armour Thyroid, Allergan, a natural thyroid extract that contains T4 and T3), and LT3 monotherapy.

There were 389 respondents, representing 20% of the ATA membership in 2017. Most were endocrinologists (84%) and 5% were surgeons; 64% were from North America and 18% were practicing in Europe.

In an analysis first looking at patient characteristics associated with prescription of combination therapy, published online November 12 in Thyroid, the authors report that key significant factors were patients' symptoms, T3 levels, thyroid-stimulating hormone levels, presence of a polymorphism, and the patient's request for T3 therapy (P < .0001 for each).

Prescription of a T3-containing therapy was meanwhile significantly less likely if patients were older or had a comorbidity (P < .0001 and P < .0002, respectively).

In a subsequent analysis looking at the characteristics of physicians, published online December 17 in Thyroid, the authors found that, after multivariate analysis, only a physician's country of practice was a significant factor in willingness to prescribe any triiodothyronine-containing therapies, with those in North America significantly more likely to do so compared with those in other countries (P < .0001).

Physicians in North America were more likely to add LT3 to LT4 (odds ratio [OR], 1.9) and to prescribe LT3 or desiccated thyroid extract monotherapy (OR, 1.7).

Of note, treatment of hypothyroidism with desiccated thyroid extract, though often requested by patients, is not supported in any of the North American or European guidelines mentioned in the survey.

Notable Shift in Prescribing Over Just a Few Years

The findings reflect a notable shift in prescribing patterns since 2013, when a comprehensive survey of 880 endocrinologists showed only 0.8% of respondents routinely prescribed combination therapy with LT4 plus LT3 for hypothyroidism, with just 3.6% of respondents willing to use the approach if the patient had symptoms (J Clin Endocrinol Metab. 2014;99:2077-2085).

In contrast, the new 2017 survey shows as many as 18% to 41% of physicians indicated willingness to add LT3 therapy while reducing LT4 dose, depending on the specific scenario, and between 9% and 29% said they add LT3 therapy while maintaining the LT4 dose, again depending on the circumstances.

Jonklaas told Medscape Medical News that the European Thyroid Association guidelines, which support the consideration of combination therapy under certain circumstances, were published in 2012 but may not have been fully assimilated at the time of the 2013 survey.

Meanwhile, guidelines of the Italian Association of Clinical Endocrinologists and Italian Thyroid Association, which also support consideration of the combination approach in selected cases, were published in 2016 and may have further influenced decision-making, she speculated.

Availability of and Accessibility to LT3 May Also Play a Role

Jonklaas added that varying accessibility to LT3 could also influence prescribing practices.

"Definitely LT3 availability may be an important factor," she said. "We did not include a question in the survey about LT3 availability in the country that the physician was practicing, but it would have been helpful if we had done so," she acknowledged.

LT3 has generally been available in the UK, for example, but patients report inconsistent coverage under the National Health Service.

"It is definitely possible that more patients request LT3 in the United States, or factors like media exposure or cost may be in operation," she added.

Another surprise was that generational differences in physicians were not seen in the prescribing of combination therapy.

"We would have predicted that younger physicians, or physicians who had more recently completed their training, would have been more willing to prescribe LT3," Jonklaas said.

"The univariate analysis actually suggested an opposite finding that physicians who had been in practice longer were more likely to prescribe LT3, but this did not hold true in multivariate analysis."

Importantly, however, the reduced prescribing of combination therapy in older patients and those with comorbidities shows a cautious approach — and awareness of the potential risks of combination therapy.

"The main risks would be cardiac arrhythmias and decreased bone density — both risks that are of more concern in older patients or patients with other health problems," Jonklaas explained.

"[Furthermore], pregnant women should not be prescribed LT3, as T4 is what is transferred from a mother to her fetus."

Much Still Misunderstood Regarding Treatment of Hypothyroidism

In a recent perspective article published in Medscape, Angela M. Leung, MD, assistant professor of medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, California, delves into the "Love-Hate Relationship With Levothyroxine," and the pros and cons in the ongoing debate over combination LT4/LT3 therapy.

She concludes: "I discuss with patients that although hypothyroidism is one of the most common medical conditions, much about treatment remains incompletely understood and my recommendations are based on the scientific evidence currently available."

The authors have reported no relevant financial relationships.

Thyroid. Published online November 12 and December 17, 2018. Abstract 1, Abstract 2